CN1715283A

CN1715283A - Neogambogic acid derivative and its production and use

Info

Publication number: CN1715283A
Application number: CN 200410025719
Authority: CN
Inventors: 段文虎; 周云隆; 蒋华良; 丁健; 罗小民; 陈奕
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2004-07-02
Filing date: 2004-07-02
Publication date: 2006-01-04

Abstract

The present invention relates to have novel neogambogic acid derivative as structure and uses thereof, formula I or formula II or formula III are through pharmacological screening, and this neogambogic acid derivative has good antineoplastic activity, and the present invention also provides the preparation method of this derivative.

Description

Neogambogic acid derivative and preparation method and application thereof

Technical Field

The invention relates to a novel neogambogic acid derivative with improved antitumor activity and application thereof as an antitumor disease medicament. The invention also relates to a preparation method of the neogambogic acid derivative.

Background

Garcinia cambogia is a colloidal resin that flows out after the trunk of Garcinia banburyi (Garcinia banburyi) which is a plant of Guttiferae is cut. Mainly produced Cambodia, Thailand and Vietnam, and cultivated in Guangdong province and Hainan province of China. Gamboge is a mixture of 70-80% resin, 15-25% gum, etc. Wherein the Gambogic acid (Gambogic acid) is 22.75-36.59%, neogambogic acid (neogambogic acid), alloGambogic acid (alloGambogic acid) and other components (Chinese wild plant resource 22 (1): 1, 2003). In the traditional Chinese medicine, gamboge is used for counteracting toxic substances, relieving swelling, removing putrefaction, healing sores, stopping bleeding and killing parasites. It can be used for treating carbuncle, cellulitis, toxic swelling, ulcer, eczema, tumor, intractable tinea, traumatic injury, traumatic hemorrhage, and scald. It is used as diuretic abroad to treat edema and cerebral hemorrhage and lower blood pressure, etc., and is collected in the tenth edition of the United states pharmacopoeia. In recent 20 years, a great deal of research work has been done on gamboge and gambogic acid and other active ingredients thereof at home and abroad, particularly scholars in China, and the gamboge and gambogic acid and the like are found to have remarkable curative effect on tumor, small toxic and side effects and stable properties of the active ingredients, thereby attracting attention. In recent years, it has been reported that gamboge prepared into injection has a certain curative effect on malignant tumor (Tianjin pharmaceutical oncology supplement 8: 230, 1981; tetrahedron 21: 1453, 1965; Jiangxi medical college declaration 2: 1, 1980). Studies of Gambogic atlas and the like in 1984 and 1986 on the response of gambogic acid to Hela cells and ascitic liver cancer cells in miceThe results of the effect of cycle migration show that 1.8 mug/ml and 3 mug/ml gamboge has obvious inhibition effect on the growth of Hela cells. Dongcheng et al can effectively kill liver cancer cells by using 5 μ g/ml gambogic acid for 24hr, and its anticancer effect is positively correlated with drug concentration and action time (Chinese tumor clinic, 21: 464, 1994). Experiments in 1991 show that neogambogic acid has the characteristics of wide anticancer spectrum and low toxicity. Neogambogic acid on murine leukemia L compared to gambogic acid₁₂₁₀The inhibiting effect of the gambogic acid is better than that of the gambogic acid, the maximum survival time prolonging rate can reach 292 percent, and the maximum gambogic acid can only reach 119 percent. Study of Neogambogic acid on L by Microspectrophotometry₁₂₁₀The leukemia cell cycle influence shows that the neogambogic acid (intravenous drip, 10mg/kg) can reduce S-phase cells, increase G1-phase cells and generate a new cell peak at a lower channel, thereby indicating thatthe neogambogic acid can inhibit the progression of G1-S-phase cells; in addition, Neogambogic acid (10m/kg) was added to L₁₂₁₀The RNA content of the cells is also significantly reduced. (pharmaceutical reports 19 (8): 636, 1984; Chinese tumor clinic, 18 (1): 50, 1991). In addition, as an effective component of common traditional Chinese medicine gamboge, the neogambogic acid has abundant sources in the nature, and the factors enable the application of the neogambogic acid in the aspect of anti-tumor treatment to have great prospects.

Disclosure of Invention

The invention aims to design and synthesize a novel neogambogic acid derivative with good antitumor activity, thereby opening up a way for searching a lead compound for antitumor drug research or an antitumor drug. It is another object of the present invention to provide a process for preparing such derivatives.

The structure of neogambogic acid is as follows:

the specific structure of the neogambogic acid derivative of the present invention can be represented by the following structural formula I or II or III:

wherein R is³Is hydrogen; c₁-C₁₀Alkyl substituted acyl or aryl substituted acyl: among them, formyl, acetyl, carbamoyl, benzoyl and phenylacetyl are preferable;

R²is any one of the following substituent groups:

(a) hydrogen;

(b) straight or branched C₁-C₁₀Alkyl of (3), preferably C₁-C₆Alkyl of (2), preferably C₁-C₁₀Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, octyl;

(c)C₃-C₈cycloalkyl, of which cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl are preferred;

(d) aryl or C₁-C₁₀Alkyl substituted aryl, preferably benzyl and phenethyl;

(e) heteroaryl, preferably furyl, pyranyl, 2H-pyrrolyl, imidazolyl, pyrazolyl and pyridyl;

(f)C₁-C₁₀alkyl substituted acyl or aryl substituted acyl: among them, formyl, acetyl, carbamoyl, benzoyl and phenylacetyl are preferable;

represents a double or single bond, X²Is oxygen, at this time C12 and X²Form a double bond or X between²Is hydroxy when C12 is present with X²Form a single bond therebetween;

R¹³is any one of the following substituent groups:

(a) straight or branched C₁-C₁₀Alkyl of (3), preferably C₁-C₆Wherein is preferably C₁-C₁₀The alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, octyl；

(b)C₃-C₈Cycloalkyl, with cyclohexyl, cyclopentyl being preferred;

(c) straight or branched C₂-C₁₀Alkenyl or C₃-C₁₀The cycloalkenyl group of (1), wherein vinyl, butenyl, hexenyl, cyclohexenyl, cyclopentenyl are preferred;

(d) phenyl or C₁-C₁₀Alkyl-substituted phenyl: among them, preferred are phenyl, benzyl, phenethyl and phenylpropyl;

(e)C₂-C₆alkynyl of (a), wherein butynyl and hexynyl are preferred;

(f) the nucleophilic reagent containing secondary amine group includes linear or branched alkylamino group, linear or branched alkenylamino group, aromatic or aromatic alkylamino group, amine obtained by adding alkynylamino group and α, β -unsaturated ketone, wherein the preferable secondary amine nucleophilic reagent includes morpholinyl, piperidyl and piperazinyl;

R¹is any one of the following substituent groups:

(1)

wherein R is⁴Is any one of the following groups:

(a) hydrogen;

(b) straight or branched C₁-C₁₀Wherein the alkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, octyl, and the substituents in the substituted alkyl group are optionally selected from 1 to 3 of the following groups: oxy, halogen, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀Alkoxyacyl, aryloxy;

(c)C₃-C₈among them, preferred are cyclohexyl, cyclopentyl and cyclopropyl;

(d) c substituted by 1, 2 or 3 hetero atoms₁-C₁₀Preferred heteroalkyl groups include-CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂OCH₂CH₃、-CH₂CH₂NHCH₃、-CH₂CH₂N(CH₂CH₃)₂、-CH₂CH₂OCH₂CH₂NCH₃、-CH₂CH₂OCH₂CH₂OCH₂CH₂NHCH₃、-CH₂CH₂NHCH₂CH₃、-CH₂C(CH₃)CH₂N(CH₃)、-CH₂(N-ethyltetrahydropyrrole), tetrahydropyrrolyl, piperidinyl, morpholinyl;

(e) an aromatic alkyl group: comprising C substituted by aromatic groups₁-C₁₀Alkyl and substituted aryl C₁-C₁₀Among the alkyl groups substituted by aromatic groups, benzyl, phenethyl and phenylpropyl are preferred, and the substituent in the substituted aromatic group is selected from 1 to 3 of the following groups: acyl, -OCH₂O-, halogen, haloalkyl, aryl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀An alkoxy group;

(f) an aryl-heteroaryl group: comprising C substituted by an aromatic hetero group₁-C₁₀Alkyl and C substituted by substituted heteroaryl₁-C₁₀Alkyl, wherein the heteroaryl is optionally selected from one of the following groups: thienyl, furyl, 2H-pyrrolyl, imidazolyl, pyridyl. The substituent in the substituted aryl is optionally selected from one of the following groups: heteroaryl, C₁-C₁₀Alkyl, aralkyl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkoxycarbonyl, carbamoyl, aryl and C₁-C₆An amine acyl group.

(g) Straight or branched C₂-C₁₀Wherein the alkenyl group is preferably vinyl, butenyl, hexenyl, and the substituents in the substituted alkenyl group are optionally selected from 1 to 3 of the following groups: oxy, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀A heteroalkyl group;

(h)C₄-C₁₀the cycloalkenyl group of (1), wherein cyclohexenyl and cyclopentenyl are preferred;

(i)C₄-C₁₀wherein the alkynyl is preferably butynyl or hexynyl, and the substituents in the substituted alkynyl are optionally selected from 1 to 3 of the following groups: oxy, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀A heteroalkyl group;

(2)

wherein R is⁶、R⁵Independently from any one of the following substituents:

(a) hydrogen;

(b) straight or branched C₁-C₁₀Wherein the alkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, octyl, and the substituents in the substituted alkyl group are optionally selected from 1 to 3 of the following groups: hydroxy, amino, C₁-C₁₀Alkylamino, oxy, halogen, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀Alkoxyacyl, aryloxy;

(c)C₃-C₈among them, preferred are cyclohexyl, cyclopentyl and cyclopropyl;

(e) an aromatic alkyl group: comprising C substituted by aromatic groups₁-C₁₀Alkyl and substituted aryl C₁-C₁₀Among the alkyl groups substituted by aromatic groups, benzyl, phenethyl and phenylpropyl are preferred, and the substituent in the substituted aromatic group is selected from 1 to 3 of the following groups: acyl, -OCH₂O-, halogen, haloalkyl, hydroxy, amino, C₁-C₁₀Alkylamino radical, aryl radical, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀An alkoxy group;

(g) Straight or branched C₂-C₁₀Wherein the alkenyl group is preferably vinyl, butenyl, hexenyl, and the preferred substituents in the substituted alkenyl group are optionally selected from 1 to 3 of the following groups: oxy, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀A heteroalkyl group;

in the compounds of the present invention represented by structural formula I, when R is²、R³Is hydrogen, X¹Is oxygen (in this case C12 and X)¹Form a double bond therebetween), R¹Is composed of

Wherein s, t represent the number of methylene groups and the sum of s and t may be a natural number from 2 to 10, wherein the sum of s and t is preferably 3 or 4 or 5 or 6;

m is 0 or 1 or 2 or 3;

n represents a heteroatom X³A preferred number is 0, 1, 2 or 3;

R⁸、R⁷the radicals taken are as in R⁵；

In addition, when X³When it is a tertiary nitrogen, R⁸Is oxygen, thereby reacting with X³Forming nitrogen oxides.

Or R¹Is composed of

Wherein R is⁹Is any one of the following groups: is the same as R⁵A substituent group as defined; a carbonyl group; an imino group; an oxime group;

m is 0 or 1 or 2 or 3;

X⁴is nitrogen;

n is 0 or 1 or 2 or 3;

R¹⁰the radicals taken are as in R⁵Or oxygen to react with X⁴Forming nitrogen oxides.

Or R¹Is composed of

Wherein R is¹²Is any one of the following groups: is the same as R⁵A substituent group as defined; a carbonyl group; an imino group; an oxime group;

m is 0 or 1 or 2 or 3;

X⁵is nitrogen;

n is 0 or 1 or 2 or 3;

R¹¹the radicals taken are as in R⁵Or oxygen to react with X⁵Forming nitrogen oxides.

In the present invention, said haloalkyl group includes C₁-C₁₀Groups in which the alkyl group is substituted with one or more of fluorine, chlorine, bromine and iodine, such as fluoromethyl, trifluoromethyl; said heteroatoms include N, O, S; said aryl radical is C₆-C₁₄Aromatic ring of (2), preferably C₆-C₁₀Preferred aromatic groups include phenyl, naphthyl, and the like; said heteroaryl group comprises: thienyl, furyl, pyranyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl and the like; said amino group comprising an NH group₂、-NHR₁₁、-NR₁₁R₁₂And R₁₁、R₁₂To N and other heteroatoms; said amino group also includes saturated 5-7 membered nitrogen-containing heterocyclic groups, such as piperazinyl, piperidinyl, wherein R is₁₁And R₁₂Is C₁-C₁₀Alkyl or C₃-C₈Cycloalkyl groups of (a); the halogen comprises fluorine, chlorine, bromine and iodine; said amide group includes all C₁-C₆The alkanoyl group of (a) is linked to the amino nitrogen to form a group, e.g. acetamido, propionylamino, butyrylamino, pentanoylamino, hexanoylamino and the like, and also C substituted with an aromatic group₂-C₆An amido group; said alkanoyloxy groupIncluding all C₁-C₆The alkanoyl group of (a) is linked to the amino nitrogen to form a group, e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxyAnd the like.

The compounds of the present invention also include salts of the derivatives of the present invention with various acids or bases, including organic or inorganic acids, such as: hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, mandelic acid, lactic acid, maleic acid, fumaric acid, benzoic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, acidic amino acids, and the like; bases include organic or inorganic bases such as: sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, trihydroxymethyl methylamine, basic amino acid, basic nitrogen-containing heterocycle, etc.

The invention is implemented by the following steps:

the raw material compound neogambogic acid used in the present invention is prepared from commercially available gamboge resin, and the specific preparation method is described in "journal ofJiangxi medical college" (1980 (2): 1).

Firstly, synthesizing a compound shown in a structural formula I:

the raw material compound, namely the neogambogic acid, is subjected to condensation, etherification and reduction reactions to prepare a compound V with the following structure, and the compound V and a compound R⁴OH or R⁶R⁵And (3) carrying out esterification or acylation reaction on the N to prepare the compound shown in the structural formula I:

1. the synthesis of the compound V and the salt thereof comprises the following one to three reaction operation steps, wherein the step (1) and the step (2) are independent steps without the sequence, and the step (3) is carried out after the step (1) and the step (2) are completed. The completion degree of the reaction is generally determined by TLC, and after the reaction of each step is finished, the post-treatment method generally adopted comprises extraction, washing, drying and column chromatography separation, and the final product is detected by NMR or mass spectrum.

(1) Introduction of R by condensation reaction³

With equimolar amounts of acid chloride (R)³Cl) or equimolar amounts of anhydrides ((R)³)₂O) carrying out condensation reaction with the neogambogic acid, wherein the solvent used in the reaction can be dichloromethane or tetrahydrofuran; the acid-binding agent used in the reaction can be triethylamine or pyridine; reaction ofThe temperature is generally from 20 to 40 ℃ depending on the reaction conditions of the particular compound. If a catalyst such as DMAP is added inthe reaction operation and the amount of acyl chloride or acid anhydride is increased to more than 5 times of the amount of the neogambogic acid, acylation will simultaneously occur at the phenolic hydroxyl group at C6 position to produce 4, 6-diacyl neogambogic acid.

R³The Cl synthesis method is described in the handbook of Fine organic Synthesis by use, page 122

(R³)₂The synthesis of O is described in the handbook of Fine organic Synthesis by reference to page 120

(2) Introduction of R by etherification or condensation²

When R is²Is C₁-C₁₀Alkyl or C₃-C₈In the case of cycloalkyl or aryl or heteroaryl radicals, R²The introduction of (2) adopts etherification reaction.

When R is²When the acyl group is substituted by an alkyl group or an aryl group, R²The introduction of (2) adopts condensation reaction.

Reacting a phenol at C6 with the corresponding bromide (R) in the presence of sodium carbonate, potassium carbonate or cesium carbonate²Br) or iodo (R)²I) The etherification reaction is carried out by using N, N-dimethyl acetamide (DMA) or N, N-dimethyl formamide (DMF) with certain solubility to carbonate as solvent. The reaction temperature was room temperature. If iodide is used, the reaction is carried out protected from light. Because of the presence of the acid at the C30 position, an ester is also formed at the C30 position under the present conditions, and the hydrolysis is carried out under the action of lithium hydroxide and DMF as a solvent, wherein the hydrolysis temperature is 0-10 ℃.

The condensation reaction iscarried out in the same way as in step (1), wherein DMAP is added and the amount of acyl chloride or anhydride is increased to ensure that the phenol at the C6 position is acylated, but the C4 position is also acylated.

R²The synthesis of Br is described on page 117 of "New compiled organic Synthesis chemistry

R²The synthesis method of I is described in "New compiled organic Synthesis chemistry" page 136

(3) Reduction of the carbonyl group at C12 in a polar solvent to give the hydroxy group

The reducing agent used in the operation step comprises sodium borohydride and lithium borohydride, the solvent comprises methanol and tetrahydrofuran, and the reaction temperature is room temperature. And adding acetone or hydrochloric acid aqueous solution to quench the reaction when the reaction is finished.

2. From compound V and compound R⁴OH or R⁶R⁵N preparation of compound I by esterification or acylation:

R⁴the C30 carboxyl group is reacted with corresponding alcohol and amine in proper solvent under the catalysis of peptide coupling agent. The peptide coupling agent is 2 times of 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (EDC or EDCI) or Dicyclohexylcarbodiimide (DCC). Inert solvents or diluents used include dichloromethane, chloroform, tetrahydrofuran, acetonitrile, DMF, DMA, and the like. The reaction temperature is generally from 0 to 40 ℃. The preferred reaction conditions are to add 1.5 times the amount of catalyst such as 4-N, N-lutidine (DMAP), N-Hydroxybenzotriazole (HOBT). After the reaction is finished, water is added into the reaction to destroy the peptide coupling agent and the catalyst, TLC is usually used for tracking and determining the completion degree of the reaction, the post-treatment method generally comprises extraction, washing, drying, column chromatography separation and the like, and the final product is detected by NMR or mass spectrometry.

When R is¹Is an ester group (i.e. COR)⁴) When this is the case, it is also possible to use compounds of the formula V with R⁴Br or R⁴The compound I is subjected to condensation reaction under weak alkaline. The weak base is sodium bicarbonate or potassium bicarbonate. The solvent or diluent used may be acetone, DMF or DMA. The reaction is smooth at room temperatureThe method is easy to carry out. TLC is used for tracking and determining the completion degree of the reaction, and post-treatment methods generally adopted after the reaction comprise extraction, washing, drying, column chromatography separation and the like. Yield of the reaction according to R⁴The properties of the OH compound vary and the final product is confirmed by NMR or mass spectrometry.

R⁴The synthesis of OH is described in "New compiled organic Synthesis chemistry" on page 163

R⁶R⁵The synthesis of N is described in "New compiled organic Synthesis chemistry" on page 556

R⁴The synthesis of Br is described on page 117 of "New compiled organic Synthesis chemistry

R⁴The synthesis method of I is described in "New compiled organic Synthesis chemistry" page 136

Secondly, synthesizing a compound shown in a structural formula II:

under alkaline conditions, 30% hydrogen peroxide is added to the double bond connecting the C9-C10 position of the neogambogic acid with carbonyl to generate epoxide. The reaction solvent is selected from water solvent, such as sodium hydroxide water solution. The reaction temperature is room temperature, the reaction time is within 10 to 30 minutes, the reaction is quenched by 1N hydrochloric acid aqueous solution after the reaction is finished, the post-treatment method comprises extraction, washing, drying, column chromatography separation and the like, and the final product is detected by NMR or mass spectrum.

Thirdly, synthesizing the compound shown in the structural formula III:

1. preparation of organic copper compound:

by organomagnesium compounds R¹³MgX and cuprous iodide react for two hours at the temperature of between 40 ℃ below zero and 30 ℃ below zero, and tetrahydrofuran is used as a solvent for the reaction.

Organomagnesium compound R¹³MgX can be reacted with the corresponding bromide (R)¹³Br) or iodo (R)¹³I) By reaction with magnesium in diethyl ether or tetrahydrofuran, the reaction temperature being selected according toThe solvent is determined, the reaction system needs to be slightly boiled, some compounds need to be initiated by adding a small amount of iodine, and the reaction is considered to be finished when the magnesium is completely dissolved.

2. Preparation of Compound III

R¹³The introduction of (A) is carried out by carrying out 1, 4 addition reaction on double bonds connected with carbonyl at C9-C10 positions of the neogambogic acid by using an organic copper reagent. Reacting the prepared organic copper reagent with neogambogic acid, wherein the reaction solvent is tetrahydrofuran, the reaction temperature is-20 ℃, the reaction is tracked by TLC, after the reaction is finished, the reaction is quenched by hydrochloric acid aqueous solution, the post-treatment method comprises extraction, drying, column chromatography separation and the like, and the final product is detected by NMR or mass spectrometry.

Advantageous effects

The invention designs and synthesizes a novel neogambogic acid derivative, has good anti-tumor activity and can be used for preparing anti-tumor medicaments. The compound of the invention is safe and easy to prepare.

Detailed Description

The invention will now be further illustrated, but is not limited, by the following specific examples.

In the following examples, Neogambogic acid was prepared from a commercially available gamboge resin according to the methods of journal of the Jiangxi college of medicine (1980 (2): 1): grinding 100 g, adding acetone 500ml, refluxing for half an hour, repeating for three times, mixing extractive solutions, and concentrating to dryness to obtain mixture containing gambogic acid and neogambogic acid as main components, i.e. total gambogic acid. Performing column chromatography on total gambogic acid, wherein the eluent is chloroform, methanol and diethylamine which are 15: 1, and taking a brilliant yellow color band which is the neogambogic acid.

Example 1

Neogambogic acid methyl ester

Sequentially adding 20mg of neogambogic acid into a 10ml reaction bottle; sodium bicarbonate 6.5mg, N, N-Dimethylacetamide (DMA)1ml, methyl iodide 15. mu.l. After stirring reaction for 18h at room temperature in the dark, the reaction solution was poured into 50ml of water, extracted with diethyl ether (3 × 20ml), the ether layers were combined, washed three times with 150ml of salt water, dried over anhydrous sodium sulfate and evaporated to remove the solvent, the crude product was chromatographed on silica gel, eluent was ethyl acetate to petroleum ether 1: 12, and 9mg of orange yellow gum was obtained by elution.

MS：658.¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.72(s，3H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H).

Example 2

6-methoxy neogambogic acid methyl ester

Sequentially adding 20mg of methyl neogambogicate into a 25ml reaction bottle; potassium carbonate 12mg, DMA1ml, methyl iodide 15. mu.l. After stirring reaction for 18h at room temperature in the dark, the reaction solution was poured into 50ml of water, extracted with diethyl ether (3 × 20ml), the ether layers were combined, washed three times with 60ml of water, dried over anhydrous sodium sulfate and evaporated to remove the solvent, the crude product was chromatographed on silica gel, and the eluent was ethyl acetate to petroleum ether 1: 12 to obtain 12mg of orange yellow gum.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.72(s，3H)，3.66(s，3H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H).

Example 3

Neogambogic acid ethyl ester

Sequentially adding 20mg of neogambogic acid into a 10ml reaction bottle; sodium bicarbonate 6.5mg, N, N-dimethylacetamide 1ml, ethyl bromide 20. mu.l. After stirring and reacting for 18h at room temperature, the reaction solution was poured into 50ml of water, extracted with diethyl ether (3 × 20ml), the ether layers were combined, washed three times with 150ml of salt water, dried over anhydrous sodium sulfate, the solvent was evaporated, the crude product was chromatographed on silica gel, and the eluent was ethyl acetate/petroleum ether (1: 12), and eluted to give 9mg of orange yellow gum.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.8-3.9(m，2H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.4(t，J＝，3H)，1.28(s，3H).

Example 4

6-Ethoxyneogambogic acid ethyl ester

In a 10ml reaction flask, 20mg of neogambogic acid, 6mg of anhydrous potassium carbonate, 1ml of N, N-dimethylacetamide and 20. mu.l of bromoethane were sequentially added. Reacting at room temperature for 4.5h, adding anhydrous potassium carbonate 6mg and bromoethane 20 μ l, stirring at room temperature for 18h, pouring the reaction solution into 50ml of water, extracting with diethyl ether (3 × 20ml), combining ether layers, washing with 150ml of salt water for three times, drying with anhydrous sodium sulfate, evaporating to remove the solvent, performing silica gel column chromatography on the crude product, and eluting with ethyl acetate and petroleum ether at a ratio of 1: 12 to obtain 9mg of orange yellow jelly.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.8-3.9(m，4H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.4(t，J＝，6H)，1.28(s，3H).

Example 5

4-acetyl neogambogic acid

Sequentially adding 20mg of neogambogic acid into a 10ml reaction bottle; 20. mu.l of anhydrous pyridine. The salt was formed by stirring at room temperature for 1 hour. Adding acetic anhydride 20 μ l and anhydrous tetrahydrofuran, reacting at 40 deg.C for 10h, adding 2ml warm water into the reaction solution, extracting with ethyl acetate (3 × 30ml), combining ester layers, washing with 1N hydrochloric acid aqueous solution 20ml twice, drying with anhydrous sodium sulfate, evaporating to remove ethyl acetate, performing silica gel column chromatography on the crude product, and eluting with ethyl acetate and petroleum ether at ratio of 1: 8 to obtain 7mg orange yellow gum.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.6(s，3H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H).

Example 6

New gamboges acylpiperidines

Adding 15.6mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane is cooled to zero degree in ice bath, and a solution prepared by 6mg of 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (EDCI), 3.6mg of 1-Hydroxybenzotriazole (HOBT), 4.8 mu l of anhydrous piperidine and 0.4ml of dichloromethane is added dropwise. Naturally heating to room temperature, stirring and reacting for 8h, and stopping. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 10ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 5mg of yellow colloid.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.5-3.6(t，J＝4，4H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.4-1.5(m，6H)，1.28(s，3H).

Example 7

Novel gamboge diacetyl amine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 10. mu.l of diethylamine and 0.5ml of dichloromethane was addeddropwise while cooling to zero in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H)，1.0(s，6H)

Example 8

New gamboge acyl morpholine

Adding 15.6mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared by EDCI10mg, HOBT 6mg, morpholine 5. mu.l and 0.4ml of dichloromethane was added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring for 12h, adding HOBT 3mg and morpholine 5 μ l, reacting for 4h, and stopping. The reaction solution was diluted with 50ml of dichloromethane, washed twice with 10ml of saturated aqueous sodium bicarbonate solution, washed three times with 30ml of saturated saline solution, dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was subjected to silica gel column chromatography with chloroform/ethyl acetate (eluent: 8: 1) to give 5mg of an orange-yellow colloid.

¹H-NMR：7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，3.6-3.7(m，4H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H).

Example 9

12-Hydroxyneogambogic acid

Adding 20mg of neogambogic acid into a 10ml reaction bottle; after complete dissolution in 4ml of methanol, the ice salt bath was cooled to-5 ℃. 44mg of sodium borohydride was added. Reacting for 1h under a dry environment, naturally heating to room temperature, completing the reaction after 3h, adding 3N hydrochloric acid aqueous solution 2ml to quench the reaction, diluting the reaction solution with 50ml of ethyl acetate, washing twice with 0.5N hydrochloric acid aqueous solution 10ml, washing the ethyl acetate solution twice with saturated saline solution 20ml, drying with anhydrous sodium sulfate, evaporating the solvent, performing silica gel column chromatography on the crude product, and eluting to obtain 9mg of orange yellow jelly, wherein the eluent is ethyl acetate and dichloromethane which is 1: 4.

¹H-NMR：12(s，1H)，7.59(d，J＝7，1H)，5.94(t，J＝7，1H)，5.2-5.3(m，1H)，5.0-5.1(m，2H)，4.1-4.3(m，1H)，3.5(t，J＝4，1H)，3.2-3.4(m，6H)，2.9(d-d，J＝8-6，1H)，2.5(d，J＝9，1H)，2.32(d-d，J＝9-5，1H)，1.98-2.10(m，4H)，1.77(s，2H)，1.72(s，3H)，1.65(s，6H)，1.64(s，3H)，1.56(s，9H)，1.28(s，3H)。

Example 10

9, 10-Epoxineo gambogic acid

Sequentially adding 50mgof neogambogic acid into a 10ml reaction bottle; 2N sodium hydroxide 0.50ml, H₂O₂0.2ml, reaction at room temperature for 10 minutes, extraction of the aqueous layer with ethyl acetate (3 x 20ml), combination of ethyl acetate layers, three-fold washing with 60ml of 1.0N aqueous hydrochloric acid, two-fold washing with 30ml of saturated saline, drying over anhydrous sodium sulfate, evaporation of the solvent, chromatography of the crude product on silica gel, elution with ethyl acetate to petroleum ether at 1: 3 to obtain 12mg of orange yellow gum. MS: 662.3

Example 11

Novel gamboge n-butylamine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of methylene chloride, and a solution prepared by adding EDCI10mg, 4.5mg of HOBT, 6. mu.l of n-butylamine and 0.5ml of methylene chloride dropwise thereto under cooling in an ice bath to zero. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at 1: 8: 1 as eluent to give 7mg of yellow colloid. MS: 701.4

Example 12

Novel gamboge undecanamide

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, HOBT 4.5mg, n-undecane amine 10mg and 0.5ml of dichloromethane was added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at 1: 8: 1 as eluent to give 7mg of yellow colloid. MS: 799.5

Example 13

New gamboge acyl isopropyl amine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 5. mu.l of isopropylamine and 0.5ml of dichloromethane is added dropwise when the mixture is cooled to zero in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate to petroleum ether as eluent in a ratio of 1: 8 to give 7mg of yellow colloid. MS: 687.4

Example 14

Novel gamboge acyl dipropylamine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared by EDCI10mg, 4.5mg of HOBT, 8. mu.l of dipropylamine and 0.5ml of dichloromethane were added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 730.4

Example 15

Novel gamboges isobutyramide

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared by EDCI10mg, 4.5mg of HOBT, 6. mu.l of isobutylamine and 0.5ml of dichloromethane was added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 701.4

Example 16

New gamboges acyl (2, 6-dimethyl piperidine)

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 8. mu.l of 2, 6-dimethylpiperidine and 0.5ml of dichloromethane are added dropwise when the mixture is cooled to zero in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was subjected to silica gel column chromatography, eluting with ethyl acetate and benzene at a ratio of 1: 8 to give 5mg of a yellow colloid. MS: 741.4

Example 17

New gamboges tetrahydropyllioles

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 5. mu.l of pyrrolidine and 0.5ml of dichloromethane was added dropwise while cooling to zero in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was subjected to silica gel column chromatography, eluting with ethyl acetate and petroleum ether at a ratio of 1: 4 to give 6mg of yellow colloid. MS: 699.4

Example 18

Novel gambogic acid cyclohexylamine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared by EDCI10mg, HOBT 4.5mg, cyclohexylamine 7. mu.l and 0.5ml of dichloromethane were added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 726.4

Example 19

Novel gamboge acyloxyethoxyethyl amine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane is cooled to zero degree in an ice bath, and a solution prepared by EDCI10mg, 4.5mg of HOBT, 5mg of ethoxyethylamine and 0.5ml of dichloromethane is added dropwise. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at 1: 4: 1 as eluent to give 5mg of yellow colloid. MS: 717.4

Example 20

New gamboges benzamides

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, HOBT 4.5mg, benzylamine 7. mu.l and 0.5ml of dichloromethane was added dropwise while cooling tozero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at 1: 4: 1 as eluent to give 6mg of yellow colloid. MS: 735.4

Example 21

Novel gamboges acylethoxycarbonyl methylamine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane is cooled to zero degree in an ice bath, and a solution prepared from EDCI10mg, HOBT 4.5mg, glycine ethyl ester 10mg and 0.5ml of dichloromethane is added dropwise. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 731.4

Example 22

Novel gamboge acyl piperazines

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 4mg of anhydrous piperazine and 0.5ml of dichloromethane is added dropwise when the mixtureis cooled to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was subjected to silica gel column chromatography, eluting with ethyl acetate/methanol 10: 1 as eluent to give 7mg of a yellow colloid. MS: 714.4

Example 23

New gamboge acyl methyl piperazine and its citric acid salt

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of methylene chloride, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 7. mu.l of methylpiperazine and 0.5ml of methylene chloride was added dropwise thereto under cooling in an ice bath to zero degrees. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. Dissolving 71mg (0.01mmol) of neogambogic methyl piperazine in 0.2ml of ethanol, dripping 3mg (0.01mmol) of citric acid in 0.2ml of ethanol, heating to dissolve the generated precipitate, standing at room temperature to cool at room temperature to separate out a light yellow precipitate, performing suction filtration, washing a filter cake with cold ethanol, and drying to obtain 60mg of yellow neogambogic methyl piperazine citrate, wherein the MS:728.

example 24

New gamboges acyl benzyl piperazine

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane was added dropwise to a solution prepared from EDCI10mg, 4.5mg of HOBT, 11. mu.l of benzylpiperazine and 0.5ml of dichloromethane, after cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 790.4

Example 25

New gamboge acyl (4-acetyl piperazine)

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 8mg of acetylpiperazine and 0.5ml of dichloromethane was added dropwise while cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 756.4

Example 26

10-morpholinyl neogambogicylpiperidine

In a 10ml reaction flask, 20mg of neogambogic acid, 5. mu.l of morpholine and 0.5ml of tetrahydrofuran were added, and the reaction was stopped with stirring at 50 ℃ for 10 hours. The reaction mixture was diluted with 50ml of dichloromethane, washed with 50ml of saturated brine for 5 times, dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was subjected to silica gel column chromatography, and eluted with ethyl acetate and dichloromethane at a ratio of 1: 4 to give 7mg of a yellow colloid. MS: 800.5

Example 27

New gamboges acylcyclopropylamines

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 5. mu.l of cyclopropylamine and 0.5ml of dichloromethane was added dropwise thereto under cooling to zero degree in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate to petroleum ether as eluent, 1: 8 to give 8mg of yellow colloid. MS: 671.4

Example 28

New gamboges acyl (3-methoxy tetrahydropyrrole)

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane is cooled to zero degree in an ice bath, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 6mg of 3-methoxytetrahydropyrrole and 0.5ml of dichloromethane is added dropwise. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at 1: 4: 1 as eluent to give 4mg of yellow colloid. MS: 671.4

Example 29

New gamboge acyl [3- (3-methoxy) tetrahydropyrrolyl propyl]ester

Adding 20mg of neogambogic acid into a 10ml reaction bottle; 0.5ml of dichloromethane, and a solution prepared from EDCI10mg, 4.5mg of HOBT, 10mg of 3- (3-methoxytetrahydropyrrole) propanol and 0.5ml of dichloromethane is added dropwise when the mixture is cooled to zero in an ice bath. Naturally heating to room temperature, stirring and reacting for 10 h. The reaction mixture was diluted with 50ml of dichloromethane, washed twice with 20ml of 0.5N aqueous sulfuric acid, washed three times with 30ml of saturated saline, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was chromatographed on silica gel using ethyl acetate, petroleum ether and dichloromethane at a ratio of 1: 4: 1 as eluent to give 7mg of yellow colloid. MS: 787.43

Example 30

10-methyl neogambogic acid

24mg of magnesium (mmol) and 1ml of diethyl ether are added into a 5ml single-neck bottle, 0.068ml of methyl iodide (1.1mmpl) is added dropwise, the system is kept slightly boiling, and a colorless clear solution (Grignard reagent) is obtained after stirring and reacting for half an hour. Dissolving 100mg (0.5mmol) of cuprous iodide in 10ml of anhydrous tetrahydrofuran to form a suspension, cooling to-40 ℃, adding 0.1ml of self-made Grignard reagent to form yellow precipitate, stirring for reaction for 2h, allowing the yellow precipitate to disappear to form a gray suspension, and adding 20mg (0.03mmol) of neogambogic acid solution in tetrahydrofuran. Reacting at-20 deg.C for 1h, heating to room temperature, adding 1N hydrochloric acid, quenching, extracting with diethyl ether 30ml (3 × 10ml), drying, concentrating, and performing column chromatography to obtain target product 7mg orange yellow gum. MS: 662.4

Example 31 antitumor Activity assay

The antitumor activity of the synthesized compounds of the present invention was investigated by sulforhodamine B protein Staining (SRB) and tetrazolium salt (MTT) reduction, respectively (Cancer res.1988, 48(3), 589).

1. The SRB protein staining method is used for determining the inhibition effect of the compound on human lung cancer cells A-549:

SRB is a protein-binding dye that binds to basic amino acids in biological macromolecules, and its Optical Density (OD) reading at 515nm is well linear with cell number and can be used as a quantification of cell number.

1.1 test materials and instruments

Human lung cancer cell A-549 (China center for type culture Collection preservation number GDC063)

RPMI-1640 medium (Gibco Co.) containing 10% calf serum

SRB liquid (sigma company)

Tunable wavelength microplate reader (VERSAmaxTM, Molecular Device Corporation, SunnyvaleCA, USA)

Test compounds: 6-methoxy methyl neogambogic acid, ethyl 6-ethoxy neogambogic acid, 6-acetyl neogambogic acid, neogambogic acid piperidine, neogambogic acid diethylamide, neogambogic acid morpholine, 12-hydroxy neogambogic acid

Diluting the compound to be tested and the positive control neogambogic acid with dimethyl sulfoxide, wherein the concentration gradient is 10^-4M、10^-5M、10^-6M、10^-7M、10^-8M

1.2 test methods

Human lung cancer cell A-549 is cultured with RPMI-1640 containing 10% calf serum, and during measurement, the cells in logarithmic growth phase are prepared into cell suspension and inoculated onto 96-well culture plate. Adding 10 μ l of test compound with different concentrations into each well of the experimental group, adding equal volume of solvent with highest concentration (i.e. 10) into the blank control group^-4M dimethylsulfoxide) was cultured at 37 ℃ for 72 hours in 5% carbon dioxide, and then fixed with trichloroacetic acid, 100 μ l of SRB solution was added to each well, and unbound SRB was washed off, and the OD at 515nm was measured by an automated spectrophotometric plate reader. And (4) taking the tumor cell group without the medicine as a blank control, and calculating the growth inhibition rate of the medicine on the tumor cells.

Inhibition rate [ (control group OD value-administration group OD value)/control group OD value]× 100%

And (4) evaluating the result: and (4) invalidation: 10^-5mol/L＜85％；

Weak effect: 10^-5mol/L is more than or equal to 85 percent or 10^-6mol/L＞50％；

The strong effect is as follows: 10^-6mol/L is more than or equal to 85 percent or 10^-7mol/L＞50％。

1.3 test results

The results of the inhibition experiment of the compounds to be tested on the growth of A-549 tumor cells are shown in Table 1

TABLE 1 inhibition of A-549 tumor cell growth by test Compounds%

2. The inhibition effect of the compound on human leukemia cell HL-60 is determined by using an MTT reduction method:

the presence of NADP-related dehydrogenases in the mitochondria of live cells reduces yellow MTT to insoluble blue material (formazan), whereas dead cells do not. Viable cells can be counted by dissolving formazan in dimethyl sulfoxide and measuring the OD at 550nm with a microplate reader.

2.1 test materials and instruments

Human leukemia cell HL-60 (China center for type culture Collection preservation number GDC028)

RPMI-1640 medium (Gibco Co.) containing 10% calf serum

MMT liquid (sigma company)

2.2 test methods

Human lung cancer cell HL-60 was cultured in RPMI-1640 containing 10% calf serum, and cells in logarithmic phase were suspended and plated in 96-well culture plates. Adding 10 μ l of test compound with different concentrations into each well of the experimental group, adding equal volume of solvent with highest concentration (i.e. 10) into the blank control group^-4M dimethylsulfoxide) was cultured at 37 ℃ for 72 hours in 5% carbon dioxide, and then fixed with trichloroacetic acid, 100 μ l of MMT solution was added to each well, and unbound MMT was washed off, and the OD value at 550nm was measured using an automated spectrophotometric plate reader. Tumor without medicineCellsThe group is blank control, and the growth inhibition rate of the drug on the tumor cells is calculated.

Inhibition rate ═ [ (control OD value-administration OD value)/control OD value]× 100%

And (4) evaluating the result: and (4) invalidation: 10^-5mol/L＜85％；

2.3 test results

The results of the HL-60 tumor cell growth inhibition experiments with the compounds to be tested are shown in Table 2

TABLE 2 inhibition of HL-60 tumor cell growth by test Compounds%

Claims

1. A neogambogic acid derivative represented by the following structural formula I or II or III:

wherein R is³Is hydrogen; c₁-C₁₀Alkyl substituted acyl or aryl substituted acyl;

R²is any one of the following substituent groups: hydrogen; straight or branched C₁-C₁₀Alkyl groups of (a); c₃-C₈Cycloalkyl groups of (a); aryl or C₁-C₁₀An alkyl-substituted aromatic group; an aromatic hetero group; c₁-C₁₀Alkyl substituted acyl or aryl substituted acyl;

X²is oxygen, at this time C12 and X²Form a double bond or X between²Is hydroxyWhen C12 and X²Form a single bond therebetween;

R¹³is any one of the following substituent groups: straight or branched C₁-C₁₀Alkyl groups of (a); c₃-C₈Cycloalkyl groups of (a); straight or branched C₂-C₁₀Alkenyl or C₃-C₁₀Cycloalkenyl group of (a); phenyl or C₁-C₁₀Alkyl-substituted phenyl; c₂-C₆The nucleophilic reagent containing secondary amine group includes straight chain or branched chain alkylamino group, straight chain or branched chain alkenylamino group, aromatic or aromatic alkylamino group, amine obtained by adding alkynyl amine group and α, β -unsaturated ketone;

R¹is any one of the following substituent groups:

wherein R is⁴Is any one of the following groups: hydrogen; straight or branched C₁-C₁₀Or containing radicals including oxy, halogen, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀An alkyl group having 1 to 3 substituents including an alkoxyacyl group and an aryloxyl group; c₃-C₈Cycloalkyl groups of (a); c substituted by 1, 2 or 3 hetero atoms₁-C₁₀Alkyl groups of (a); arylalkyl radicals, including C substituted by aromatic radicals₁-C₁₀Alkyl and substituted or unsubstituted acyl, -OCH₂O-, halogen, haloalkyl, aryl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀Aryl substituted by alkoxy with 1 to 3 optional substituents₁-C₁₀An alkyl group; an aryl-heteroaryl group: comprising C substituted by an aromatic hetero group₁-C₁₀Alkyl and substituted or unsubstituted aryl or heteroaryl₁-C₁₀Alkyl, aralkyl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkoxycarbonyl, carbamoyl, aryl and C₁-C₆Heteroaryl substituted with an aromatic group as the substituent of any other amino group₁-C₁₀An alkyl group; straight or branched C₂-C₁₀Or containing radicals including oxy, halogen, aromatic ring radicals, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀Alkenyl of any 1 to 3 substituents inclusive of heteroalkyl; c₄-C₁₀Cycloalkenyl group of (a); c₄-C₁₀Or containing radicals including oxy, halogen, aromatic ring, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀Alkynyl of any 1 to 3 substituents inclusive of heteroalkyl;

wherein R is⁶、R⁵Independently from any one of the following substituents: hydrogen; straight or branched C₁-C₁₀Or containing radicals including hydroxy, amino, C₁-C₁₀Alkylamino, oxy, halogen, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀An alkyl group having 1 to 3 substituents including an alkoxyacyl group and an aryloxyl group; c₃-C₈Cycloalkyl groups of (a); c substituted by 1, 2 or 3 hetero atoms₁-C₁₀Alkyl groups of (a); an aromatic alkyl group: comprising C substituted by aromatic groups₁-C₁₀Alkyl and substituted or unsubstituted acyl, -OCH₂O-, halogen, haloalkyl, hydroxy, amino, C₁-C₁₀Alkylamino radical, aryl radical, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀Aryl substituted by alkoxy with 1 to 3 optional substituents₁-C₁₀An alkyl group; an aryl-heteroaryl group: comprising C substituted by an aromatic hetero group₁-C₁₀Alkyl and substituted or unsubstituted aryl or heteroaryl₁-C₁₀Alkyl, aralkyl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkoxycarbonyl, carbamoyl, aryl and C₁-C₆Heteroaryl substituted with an aromatic group as the substituent of any other amino group₁-C₁₀An alkyl group; straight or branched C₂-C₁₀Or containing radicals including oxy, halogen, aromatic ring radicals, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀Alkenyl of any 1 to 3 substituents inclusive of heteroalkyl; c₄-C₁₀Cycloalkenyl group of (a); c₄-C₁₀Or containing radicals including oxy, halogen, aromatic ring, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀Alkynyl of any 1 to 3 substituents inclusive of heteroalkyl.

2. The neogambogic acid derivative according to claim 1, wherein:

R³is any one of the following substituent groups: hydrogen; a formyl group; acetyl; a carbamoyl group; a benzoyl group; a benzoyl group; phenylacetyl;

R²is any one of the following substituent groups: hydrogen; a methyl group; an ethyl group; propyl; isopropyl group; a butyl group; an isobutyl group; a tertiary butyl group; hexyl; octyl; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cycloheptyl group; a benzyl group; a phenethyl group; a furyl group; a pyranyl group; 2H-pyrrolyl; a pyrrolyl group; an imidazolyl group; a pyrazolyl group; a pyridyl group; a formyl group; acetyl; a carbamoyl group; a benzoyl group; a benzoyl group; phenylacetyl;

R¹³is any one of the following substituent groups: a methyl group; an ethyl group; propyl; isopropyl group; a butyl group; an isobutyl group; a tertiary butyl group; hexyl; octyl; a cyclohexyl group; a cyclopentyl group; a vinyl group; a butenyl group; a hexenyl group; a cyclohexenyl group;a cyclopentenyl group; a phenyl group; a benzyl group; a phenethyl group; a phenylpropyl group; butynyl; a hexynyl group; morpholinyl; a piperidinyl group; a piperazinyl group;

R¹is any one of the following substituent groups:

wherein R is⁴Is any one of the following groups: hydrogen; a methyl group; an ethyl group; propyl; isopropyl group; a butyl group; an isobutyl group; a tertiary butyl group; hexyl; octyl; containing oxygen radicals, halogens, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀C having 1 to 3 optional substituents including alkoxyacyl group and aryloxy group₁-C₁₀An alkyl group; a cyclohexyl group; a cyclopentyl group; a cyclopropyl group; -CH₂CH₂OCH₂CH₃；-CH₂CH₂OCH₂CH₂OCH₂CH₃-CH₂CH₂NHCH₃；-CH₂CH₂N(CH₂CH₃)₂；-CH₂CH₂OCH₂CH₂NCH₃；-CH₂CH₂OCH₂CH₂OCH₂CH₂NHCH₃；-CH₂CH₂NHCH₂CH₃；-CH₂C(CH₃)CH₂N(CH₃)；-CH₂(N-ethyl tetrahydropyrrole); a tetrahydropyrrole group; a piperidinyl group; morpholinyl; a benzyl group; a phenethyl group; a phenylpropyl group; is contained including acyl group, -OCH₂O-, halogen, haloalkyl, aryl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀Aryl substituted by alkoxy with 1 to 3 optional substituents₁-C₁₀An alkyl group; a thienyl group; a furyl group; 2H-pyrrolyl; a pyrrolyl group; an imidazolyl group; a pyridyl group; is composed of an aromatic hetero group, C₁-C₁₀Alkyl, aralkyl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkoxycarbonyl, carbamoyl, aryl and C₁-C₆Any one of aminoacylHeteroaryl substituted C with one substituent₁-C₁₀An alkyl group; a vinyl group; a butenyl group; a hexenyl group; a cyclohexenyl group; a cyclopentenyl group; containing oxygen, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀C of any 1 to 3 substituents including heteroalkyl₂-C₁₀An alkenyl group; butynyl; a hexynyl group; containing oxygen, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀C of any 1 to 3 substituents including heteroalkyl₄-C₁₀An alkynyl group;

wherein R is⁶、R⁵Independently from any one of the following substituents: hydrogen; a methyl group; an ethyl group; propyl; isopropyl group; a butyl group; an isobutyl group; a tertiary butyl group; hexyl; octyl; containing a compound including hydroxy, amino, C₁-C₁₀Alkylamino, oxy, halogen, C₁-C₁₀Alkoxy, alkanoyloxy, C₁-C₁₀C having 1 to 3 optional substituents including alkoxyacyl group and aryloxy group₁-C₁₀An alkyl group; a cyclohexyl group; a cyclopentyl group; a cyclopropyl group; -CH₂CH₂OCH₂CH₃；-CH₂CH₂OCH₂CH₂OCH₂CH₃；-CH₂CH₂NHCH₃；-CH₂CH₂N(CH₂CH₃)₂；-CH₂CH₂OCH₂CH₂NCH₃；-CH₂CH₂OCH₂CH₂OCH₂CH₂NHCH₃；-CH₂CH₂NHCH₂CH₃；-CH₂C(CH₃)CH₂N(CH₃)；-CH₂(N-ethyl tetrahydropyrrole); a tetrahydropyrrole group; a piperidinyl group; morpholinyl; a benzyl group; a phenethyl group; a phenylpropyl group; is contained including acyl group, -OCH₂O-, halogen, haloalkyl, hydroxy, amino, C₁-C₁₀Alkylamino radical, aryl radical, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkyl, hydroxy, acyloxy, C₁-C₁₀Aryl substituted by alkoxy with 1 to 3 optional substituents₁-C₁₀An alkyl group; a thienyl group; a furyl group; 2H-pyrrolyl; a pyrrolyl group; an imidazolyl group; a pyridyl group; is composed of an aromatic hetero group, C₁-C₁₀Alkyl, aralkyl, C₃-C₈Cycloalkyl radical, C₁-C₁₀Alkoxycarbonyl, carbamoyl, aryl and C₁-C₆Heteroaryl substituted with an aromatic group as the substituent of any other amino group₁-C₁₀An alkyl group; a vinyl group; a butenyl group; a hexenyl group; containing oxygen, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀C of any 1 to 3 substituents including heteroalkyl₂-C₁₀An alkenyl group; a cyclohexenyl group; cyclopentenyl, butynyl; a hexynyl group; containing oxygen, halogen, aromatic ring radical, aralkyl, C₁-C₁₀Alkoxy, alkanoyloxy, amido, C₁-C₆Aminoacyl, C₁-C₁₀Alkoxyacyl, aryloxy and C containing 1, 2 or 3 hetero atoms₁-C₁₀C of any 1 to 3 substituents including heteroalkyl₄-C₁₀Alkynyl.

3. The neogambogic acid derivative according to claim 1, characterized in that the derivative is represented by the structural formula I, when R is²、R³When it is hydrogen, X¹Is oxygen (in this case C12 and X)¹With a double bond formed therebetween) is used,

R¹is composed of

Wherein the sum of s and t is a natural number from 2 to 10;

m is 0 or 1 or 2 or 3;

n is 0, 1, 2 or 3;

R⁷、R⁸the radicals taken are as in R⁵Furthermore when X³When it is a tertiary nitrogen, R⁸Is oxygen, thereby reacting with X³Forming nitrogen oxides;

or R¹Is composed of

m is 0 or 1 or 2 or 3;

X⁴is nitrogen;

n is 0 or 1 or 2 or 3;

R¹⁰the radicals taken are as in R⁴Or oxygen to react with X⁴Forming nitrogen oxides;

or R¹Is composed of

m is 0 or 1 or 2 or 3;

X⁵is nitrogen;

n is 0 or 1 or 2 or 3;

4. The salt of a neogambogic acid derivative with an acid or a base as claimed in claim 1, which comprises an inorganic acid salt, an organic acid salt, an inorganic base salt and an organic base salt of the derivative.

5. The salt of a neogambogic acid derivative with an acid or a base according to claim 4, which comprises a hydrochloride, a sulfate, a phosphate, a nitrate, an acetate, a fumarate, a maleate, a benzoate, a citrate, a methanesulfonate, a p-toluenesulfonate, a tartrate, a lactate, and salts of acidic amino acids, sodium salts, potassium salts, calcium salts, magnesium salts, basic amino acids, and basic nitrogen-containing heterocycles.

6. The process for producing a neogambogic acid derivative according to claim 1, wherein the neogambogic acid derivative is produced by condensing a neogambogic acid,Preparation of compound by etherification and reduction reactionCompound V and compound R⁴OH or R⁶R⁵Carryingout esterification or acylation reaction on N to prepare a compound shown in a structural formula I; under the alkaline condition, 30 percent of hydrogen peroxide is added to double bonds connected with carbonyl groups at C9-C10 positions of the neogambogic acid to prepare a compound shown in a structural formula II; using organic copper reagents R¹³Cu performs 1, 4 addition reaction on double bonds connected with carbonyl at C9-C10 positions of the neogambogic acid to prepare the compound shown in the structural formula III.

7. The process for the preparation of a neogambogic acid derivative according to claim 6, wherein compound V is reacted with compound R⁴OH or R⁶R⁵And in the esterification or acylation reaction of N, 4-N, N-dimethylpyridine or N-hydroxybenzotriazole is used as a catalyst.

8. Use of the neogambogic acid derivative of claim 1 as an anti-neoplastic disease agent.